DESCRIPTION OF THE OVERALL PROGRAM (taken from the application): This program project application represents a coordinated, collaborative and multidisciplinary approach that utilizes common resources, facilities and instrumentation to support scientific investigators related to the pathogenesis of osteoporosis. This application is comprised of four highly integrated scientific projects and three supporting core facilities (Administration, Molecular Histology and Transgenic Animal and Molecular Cores). The central theme of the ?program project is that the pathogenesis of osteoporosis is due both to the interaction of catabolic factors that increase bone resorption and to the loss of anabolic activities. These factors, both systemic hormones and local cytokines, modulate the differentiation of osteoclast and osteoblast lineage cells and the biological function of these cells. An understanding of these factors and their actions on bone remodeling will help elucidate the pathogenesis of osteoporosis. Moreover, intervention with molecules that block pathogenic factors or enhance anabolic activities will have therapeutic implications. This could be accomplished by somatic gene therapy once the cellular and molecular steps required to develop such a strategy are developed. The scientific projects of this application are: (1) Glucocorticoids and osteoblast apoptosis, (2) Estrogen regulation of cytokine responsiveness in bone: osteoclastogenesis, (3) The roles of insulin-like growth factor and glucocorticoids on bone remodeling, and (4) Engraftment of osteoprogenitor cells in bone. We believe that interactions among our investigators, research productivity towards the central theme and new collaborations will be facilitated greatly by the program project mechanism.